This K23 award application describes a career development plan for Dennis Hartigan-O'Connor, MD, PhD, a postdoctoral fellow in the Division of Experimental Medicine at the University of California, San Francisco. The award will provide Dr. Hartigan-O'Connor with the support required to establish himself as an independent investigator providing leadership in understanding mechanisms of immune protection against HIV and other chronic infectious diseases. In particular, the award will allow Dr. Hartigan-O'Connor to accomplish the following goals: (1) to become an expert in mechanisms of immune regulation, particularly those involving regulatory T cells; (2) to become proficient in the translational aspects of designing, funding, and carrying out clinical trials, particularly cohort studies and interventional trials; (3) to develop study design skills that will allow testing of specific hypotheses in chronically-infected human patients; (4) to develop biostatistical skills allowing proper analysis of longitudinal and interventional studies of immunomodulatory agents in HIV-infected patients; and (5) to develop an independent research career focused on immune protection against HIV. To achieve these goals, Dr. Hartigan-O'Connor has assembled a mentoring team comprised of a primary mentor, Dr. Joseph M. McCune, Chief of the Division of Experimental Medicine at San Francisco General Hospital, who conducts research into the immunopathogenesis of HIV disease, and three co-mentors: Dr. Steven Deeks, Director of the SCOPE cohort study; Dr. Jeffrey Bluestone, Director of the Immune Tolerance Network and an expert in mechanisms of immune regulation; and Dr. Jeffrey Martin, an expert in the design and statistical analysis of studies in chronically-infected patients. The goal of Dr. Hartigan-O'Connor's research project is to understand the mechanisms by which regulatory T cells (T-regs) influence T cell activation and effector immune responses in SIV/HIV-infected infants and adults. Dr. Hartigan-O'Connor will test immunoregulatory responses in infants and adults to determine whether optimal immunologic control of HIV/SIV requires a functional T-reg compartment that prevents generalized immune activation but lacks T-regs, such as HIV-specific T-regs, that interfere with virus-specific T cell responses. The aims of the proposal are to demonstrate the presence of SIV-specific suppressive activity in infected infants; to determine whether infant human T-regs exert greater control over HIV-specific CD4+ T cells than do adult T-regs; and to determine whether compromise of the functional T-reg compartment in adult humans predates and predicts subsequent loss of immunologic control. The public health problem addressed by this training proposal is failure of the body's immune responses to protect against HIV disease. Development of vaccines and therapies that protect against HIV is hampered by a limited understanding of the mechanisms by which the virus subverts effective immune responses. A long-term solution to the problem of HIV worldwide will not be found until the mechanisms that limit immune responses to the virus are understood and can be limited or controlled.